Excitatory amino acid receptor antagonists

ABSTRACT

The present invention provides novel compounds of Formula (I), or the pharmaceutically acceptable salts or prodrugs thereof, and methods for treating neurological disorders and neurodegenerative diseases, particularly pain and migraine.

BACKGROUND OF THE INVENTION

[0001] In the mammalian central nervous system (CNS), the transmissionof nerve impulses is controlled by the interaction between aneurotransmitter, that is released by a sending neuron, and a surfacereceptor on a receiving neuron, which causes excitation of thisreceiving neuron. L-Glutamate, which is the most abundantneurotransmitter in the CNS, mediates the major excitatory pathways inmammals, and is referred to as an excitatory amino acid (EAA). Thereceptors that respond to glutamate are called excitatory amino acidreceptors (EAA receptors). See Watkins & Evans, Ann. Rev. Pharmacol.Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev.Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, andHonore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acidsare of great physiological importance, playing a role in a variety ofphysiological processes, such as long-term potentiation (learning andmemory), the development of synaptic plasticity, motor control,respiration, cardiovascular regulation, and sensory perception.

[0002] Excitatory amino acid receptors are classified into two generaltypes. Receptors that are directly coupled to the opening of cationchannels in the cell membrane of the neurons are termed “ionotropic.”This type of receptor has been subdivided into at least three subtypes,which are defined by the depolarizing actions of the selective agonistsN-methyl-D-aspartate (NMDA),α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainicacid (KA). Molecular biological studies have established that AMPAreceptors are composed of subunits (GluR₁-GluR₄), which can assemble toform functional ion channels. Five kainate receptors have beenidentified which are classified as either High Affinity (KA1 and KA2) orLow Affinity (composed of GluR₅, GluR₆, and/or GluR₇ subunits). Bleakmanet al., Molecular Pharmacology, 49, No.4, 581,(1996). The second generaltype of receptor is the G-protein coupled or second messenger-linked“metabotropic” excitatory amino acid receptor. This second type iscoupled to multiple second messenger systems that lead to enhancedphosphoinositide hydrolysis, activation of phospholipase D, increases ordecreases in cAMP formation, and changes in ion channel function.Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both typesof excitatory amino acid receptor appear not only to mediate normalsynaptic transmission along excitatory pathways, but also to participatein the modification of synaptic connections during development andthroughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol.Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15,41 (1990).

[0003] The excessive or inappropriate stimulation of excitatory aminoacid receptors leads to neuronal cell damage or loss by way of amechanism known as excitotoxicity. This process has been suggested tomediate neuronal degeneration in a variety of neurological disorders andconditions. The medical consequences of such neuronal degeneration makesthe abatement of these degenerative neurological processes an importanttherapeutic goal. For instance, excitatory amino acid receptorexcitotoxicity has been implicated in the pathophysiology of numerousneurological disorders, including the etiology of cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, cerebralischemia, spinal cord lesions resulting from trauma or inflammation,perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. Inaddition, excitotoxicity has been implicated in chronicneurodegenerative conditions including Alzheimer's Disease, Huntington'sChorea, inherited ataxias, AIDS-induced dementia, amyotrophic lateralsclerosis, idiopathic and drug-induced Parkinson's Disease, as well asocular damage and retinopathy. Other neurological disorders implicatedwith excitotoxicity and/or glutamate dysfunction include muscularspasticity including tremors, drug tolerance and withdrawal, brainedema, convulsive disorders including epilepsy, depression, anxiety andanxiety related disorders such as post-traumatic stress syndrome,tardive dyskinesia, and psychosis related to depression, schizophrenia,bipolar disorder, mania, and drug intoxication or addiction (seegenerally U.S. Pat. Nos. 5,446,051 and 5,670,516). Excitatory amino acidreceptor antagonists may also be useful as analgesic agents and fortreating or preventing various forms of headache, including clusterheadache, tension-type headache, and chronic daily headache. Inaddition, published International Patent application WO 98/45720 reportsthat excitatory amino acid receptor excitotoxicity participates in theetiology of acute and chronic pain states including severe pain,intractable pain, neuropathic pain, post-traumatic pain.

[0004] It is also known that trigeminal ganglia, and their associatednerve pathways, are associated with painful sensations of the head andface such as headache and, in particular, migraine. Moskowitz(Cephalalgia, 12, 5-7, (1992) proposed that unknown triggers stimulatethe trigeminal ganglia which in turn innervate vasculature withincephalic tissue, giving rise to the release of vasoactive neuropeptidesfrom axons innervating the vasculature. These neuropeptides initiate aseries of events leading to neurogenic inflammation of the meninges, aconsequence of which is pain. This neurogenic inflammation is blocked bysumatriptan at doses similar to those required to treat acute migrainein humans. However, such doses of sumatriptan are associated withcontraindications as a result of sumatriptan's attendantvasoconstrictive properties.(see MacIntyre, P. D., et al., BritishJournal of Clinical Pharmacology, 34, 541-546 (1992); Chester, A. H., etal., Cardiovascular Research, 24, 932-937 (1990); Conner, H. E., et al.,European Journal of Phannacology, 161, 91-94 (1990)). Recently, it hasbeen reported that all five members of the kainate subtype of ionotropicglutamate receptors are expressed on rat trigeminal ganglion neurons,and in particular, high levels of GluR₅ and KA2 have been observed.(Sahara et al., The Journal of Neuroscience, 17(17), 6611 (1997)). Assuch, migraine presents yet another neurological disorder which may beimplicated with glutamate receptor excitotoxicity.

[0005] The use of a neuroprotective agent, such as an excitatory aminoacid receptor antagonist, is believed to be useful in treating orpreventing all of the aforementioned disorders and/or reducing theamount of neurological damage associated with these disorders. Forexample, studies have shown that AMPA receptor antagonists areneuroprotective in focal and global ischemia models. The competitiveAMPA receptor antagonist NBQX(2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline) has been reportedeffective in preventing global and focal ischemic damage. Sheardown etal., Science, 247, 571 (1900); Buchan et al., Neuroreport, 2, 473(1991); LePeillet et al., Brain Research, 571, 115 (1992). Thenoncompetitive AMPA receptor antagonists GKYI 52466 has been shown to bean effective neuroprotective agent in rat global ischemia models.LaPeillet et al., Brain Research, 571, 115 (1992). European PatentApplication Publication No. 590789A1 and U.S. Pat. Nos. 5,446,051 and5,670,516 disclose that certain decahydroisoquinoline derivativecompounds are AMPA receptor antagonists and, as such, are useful in thetreatment of a multitude of disorders conditions, including pain andmigraine headache. WO 98/45270 discloses that certaindecahydroisoquinoline derivative compounds are selective antagonists ofthe iGluR₅ receptor and are useful for the treatment of various types ofpain, including; severe, chronic, intractable, and neuropathic pain.

[0006] In accordance with the present invention, Applicants havediscovered novel compounds that are antagonists of the iGluR₅ receptorsubtype and, thus, could be useful in treating the multitude ofneurological disorders or neurodegenerative diseases, as discussedabove. Such antagonists could address a long felt need for safe andeffective treatments for neruological disorders, without attending sideeffects. The treatment of neurological disorders and neurodegenerativediseases is hereby furthered.

SUMMARY OF THE INVENTION

[0007] The present invention provides a compound of Formula I

[0008] wherein

[0009] R¹ is H, CO₂H, tetrazole, OH, or (C₁-C₄)alkyltetrazole;

[0010] R² is H, (C₁-C₆)alkyl, aryl, halo, CO₂H,(C₁-C₆)alkyl-heterocycle, (C₁-C₆)alkyl-(substituted)heterocycle,(C₁-C₄)alkyl-N—SO₂-aryl, NO₂, NH₂, CF₃, or (C₁-C₆)alkoxy carbonyl,NSO₂aryl;

[0011] W, X, and Y each independently represent H, (C₁-C₆)alkyl, CO₂H,halo, OH, heterocycle, substituted heterocycle, CF₃, (CH²)_(n)CO₂H,(C₁-C₆)alkoxy, or (C₁-C₆)alkoxy carbonyl;

[0012] or optionally, X and R² together, along with the carbon atoms towhich they are attached, form a fused-benzo group,

[0013] or optionally, W and R¹ together, along with the carbon atoms towhich they are attached, form a fused-benzo group or a fused-triazolegroup;

[0014] n is 0, 1, or 2,

[0015] or a pharmaceutically acceptable salt or prodrug thereof.

[0016] In another embodiment, the present invention provides a method oftreating or preventing a neurological disorder, or neurodegenerativecondition, comprising administering to a patient in need thereof aneffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof. Examples of such neurological disorders, orneurodegenerative conditions, include: cerebral deficits subsequent tocardiac bypass surgery and grafting; stroke; cerebral ischemia; spinalcord lesions resulting from trauma or inflammation; perinatal hypoxia;cardiac arrest; hypoglycemic neuronal damage; Alzheimer's Disease;Huntington's Chorea; inherited ataxias; AIDS-induced dementia;amyotrophic lateral sclerosis; idiopathic and drug-induced Parkinson'sDisease; ocular damage and retinopathy; muscular spasticity includingtremors; drug tolerance and withdrawal; brain edema; convulsivedisorders including epilepsy; depression; anxiety and anxiety relateddisorders such as post-traumatic stress syndrome; tardive dyskinesia;psychosis related to depression, schizophrenia, bipolar disorder, mania,and drug intoxication or addiction; headache, including clusterheadache, tension-type headache, and chronic daily headache; migraine;and acute and chronic pain states including severe pain, intractablepain, neuropathic pain, and post-traumatic pain.

[0017] More specifically, the present invention provides a method oftreating or preventing pain or migraine comprising administering to apatient in need thereof an effective amount of a compound of Formula I,or a pharmaceutically acceptable salt or prodrug thereof.

[0018] In addition, the present invention provides pharmaceuticalcompositions of compounds of Formula I, including the pharmaceuticallyacceptable salts, prodrugs, and hydrates thereof, comprising, a compoundof Formula I in combination with a pharmaceutically acceptable carrier,diluent or excipient. This invention also encompasses novelintermediates, and processes for the synthesis of the compounds ofFormula.

[0019] The present invention also provides the use of a compound ofFormula I for the manufacture of a medicament for treating or preventinga neurological disorder, or neurodegenerative condition.

[0020] More specifically, the present invention provides the use of acompound of Formula I for the manufacture of a medicament for treatingor preventing pain or migraine.

DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention provides compounds functional as iGluR₅receptor antagonists as well as pharmaceutically acceptable salts,prodrugs, and compositions thereof. These compounds are useful intreating or preventing neurological disorders, or neurodegenerativediseases, particularly pain and migraine. As such, methods for thetreatment or prevention of neurological disorders, or neurodegenerativediseases, are also provided by the present invention.

[0022] In addition, it should be understood by the skilled artisan thatall of the compounds useful for the methods of the present invention areavailable for prodrug formulation. As used herein, the term “prodrug”refers to a compound of Formula I which has been structurally modifiedsuch that in vivo the prodrug is converted, for example, by hydrolytic,oxidative, reductive, or enzymatic cleavage into the parent compound(e.g. the carboxylic acid (drug), or as the case may be the parentdicarboxylic acid (drug)) as given by Formula I. Such prodrugs may be,for example, metabolically labile mono- or di-ester derivatives of theparent compounds having a carboxylic acid group. It is to be understoodthat the present invention includes any such prodrugs, such asmetabolically labile ester or diester derivatives of compounds of theFormula. In all cases, the use of the compounds described herein asprodrugs is contemplated, and often is preferred, and thus, the prodrugsof all of the compounds provided are encompassed in the names of thecompounds herein. Conventional procedures for the selection andpreparation of suitable prodrugs are well known to one of ordinary skillin the art.

[0023] More specifically, examples of prodrugs of Formula I which areunderstood to be included within the scope of the present invention, arerepresented by Formulas Ia below:

[0024] wherein

[0025] R³ is hydrogen, (C₁-C₂₀)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkylaryl,(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-N,N—C₁-C₆ dialkylamine,(C₁-C₆)alkyl-pyrrolidine, (C₁-C₆)alkyl-piperidine, or(C₁-C₆)alkyl-morpholine;

[0026] R⁴ is H, CO₂R⁶, tetrazole, OH, or (C₁-C₄)alkyltetrazole;

[0027] R⁵ is H, (C₁-C₆)alkyl, aryl, halo, CO₂R⁷,(C₁-C₆)alkyl-heterocycle, (C₁-C₆)alkyl-(substituted)heterocycle,(C₁-C₄)alkyl-N—SO₂-aryl, NO₂, NH₂, CF₃, (C₁-C₆)alkoxy carbonyl, orNSO₂aryl;

[0028] W′, X′, and Y′ each independently represent H, (C₁-C₆)alkyl,CO₂R⁸, halo, OH, heterocycle, substituted heterocycle, CF₃,(CH₂)_(n)CO₂R⁸, (C₁-C₆)alkoxy or (C₁-C₆)alkoxy carbonyl;

[0029] R⁶, R⁷, and R⁸ each independently represent hydrogen,(C₁-C₂₀)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkylaryl,(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-N,N—C₁-C₆ dialkylamine,(C₁-C₆)alkyl-pyrrolidine, (C₁-C₆)alkyl-piperidine, or(C₁-C₆)alkyl-morpholine;

[0030] or optionally, X′ and R⁵ together, along with the carbon atoms towhich they are attached, form a benzo-fused group,

[0031] or optionally, W′ and R⁴ together, along with the carbon atoms towhich they are attached, form a benzo-fused group or a triazole-fusedgroup, and

[0032] n is 0, 1, or 2;

[0033] with the proviso that where R⁴ is CO₂R⁶, or R⁵ is CO₂R⁷, or W′,X′, or Y′ is CO₂R⁸ then at least one, but no more than two of R³, R⁶,R⁷, and R⁸ is other than hydrogen;

[0034] or a pharmaceutically acceptable salt thereof.

[0035] It is understood that the iGluR5 receptor antagonists of thepresent invention may exist as pharmaceutically acceptable salts and, assuch, salts are therefore included within the scope of the presentinvention. The term “pharmaceutically acceptable salt” as used herein,refers to salts of the compounds provided by, or employed in the presentinvention which are substantially non-toxic to living organisms. Typicalpharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with apharmaceutically acceptable mineral or organic acid or an organic orinorganic base. Such salts are known as acid addition and base additionsalts.

[0036] It will be understood by the skilled reader that most or all ofthe compounds used in the present invention are capable of formingsalts, and that the salt forms of pharmaceuticals are commonly used,often because they are more readily crystallized and purified than arethe free bases. In all cases, the use of the pharmaceuticals describedherein as salts is contemplated in the description herein, and often ispreferred, and the pharmaceutically acceptable salts of all of thecompounds are included in the names of them.

[0037] Acids commonly employed to form acid addition salts are inorganicacids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide,hydroiodide, dihydroiodide, acetate, propionate, decanoate, caprylate,acrylate, formate, hydrochloride, dihydrochloride, isobutyrate,caproate, heptanoate, propiolate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate,phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,α-hydroxybutyrate, glycolate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate,mandelate and the like. Preferred pharmaceutically acceptable acidaddition salts are those formed with mineral acids such as hydrochloricacid and hydrobromic acid, and those formed with organic acids such asmaleic acid, mandelic acid, and methanesulfonic acid.

[0038] Base addition salts include those derived from inorganic bases,such as ammonium or alkali or alkaline earth metal hydroxides,carbonates, bicarbonates, and the like. Such bases useful in preparingthe salts of this invention thus include sodium hydroxide, potassiumhydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate,sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. The potassium and sodium salt forms areparticularly preferred. It should be recognized that the particularcounterion forming a part of any salt of this invention is usually notof a critical nature, so long as the salt as a whole ispharmacologically acceptable and as long as the counterion does notcontribute undesired qualities to the salt as a whole. It is furtherunderstood that such salts may exist as a hydrate.

[0039] As used herein, the term “stereoisomer” refers to a compound madeup of the same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

[0040] The term “enantiomeric enrichment” as used herein refers to theincrease in the amount of one enantiomer as compared to the other. Aconvenient method of expressing the enantiomeric enrichment achieved isthe concept of enantiomeric excess, or “ee”, which is found using thefollowing equation:${e\quad e} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$

[0041] wherein E¹ is the amount of the first enantiomer and E² is theamount of the second enantiomer. Thus, if the initial ratio of the twoenantiomers is 50:50, such as is present in a racemic mixture, and anenantiomeric enrichment sufficient to produce a final ratio of 50:30 isachieved, the ee with respect to the first enantiomer is 25%. However,if the final ratio is 90:10, the ee with respect to the first enantiomeris 80%. An ee of greater than 90% is preferred, an ee of greater than95% is most preferred and an ee of greater than 99% is most especiallypreferred. Enantiomeric enrichment is readily determined by one ofordinary skill in the art using standard techniques and procedures, suchas gas or high performance liquid chromatography with a chiral column.Choice of the appropriate chiral column, eluent and conditions necessaryto effect separation of the enantiomeric pair is well within theknowledge of one of ordinary skill in the art. In addition, theenantiomers of compounds of Formula I can be resolved by one of ordinaryskill in the art using standard techniques well known in the art, suchas those described by J. Jacques, et al., “Enantiomers, Racemates, andResolutions”, John Wiley and Sons, Inc., 1981.

[0042] The compounds of the present invention have one or more chiralcenters and may exist in a variety of stereoisomeric configurations. Asa consequence of these chiral centers, the compounds of the presentinvention occur as racemates, mixtures of enantiomers and as individualenantiomers, as well as diastereomers and mixtures of diastereomers. Allsuch racemates, enantiomers, and diastereomers are within the scope ofthe present invention.

[0043] The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

[0044] The specific stereoisomers and enantiomers of compounds ofFormula I can be prepared by one of ordinary skill in the art utilizingwell known techniques and processes, such as those disclosed by Elieland Wilen, “Stereochemistry of Organic Compounds”, John Wiley & Sons,Inc., 1994, Chapter 7, Separation of Stereoisomers. Resolution.Racemization, and by Collet and Wilen, “Enantiomers, Racemates, andResolutions”, John Wiley & Sons, Inc., 1981. For example, the specificstereoisomers and enantiomers can be prepared by stereospecificsyntheses using enantiomerically and geometrically pure, orenantiomerically or geometrically enriched starting materials. Inaddition, the specific stereoisomers and enantiomers can be resolved andrecovered by techniques such as chromatography on chiral stationaryphases, enzymatic resolution or fractional recrystallization of additionsalts formed by reagents used for that purpose.

[0045] As used herein the term “Pg” refers to a suitable nitrogenprotecting group. Examples of a suitable nitrogen protecting group asused herein refers to those groups intended to protect or block thenitrogen group against undesirable reactions during syntheticprocedures. Choice of the suitable nitrogen protecting group used willdepend upon the conditions that will be employed in subsequent reactionsteps wherein protection is required, and is well within the knowledgeof one of ordinary skill in the art. Commonly used nitrogen protectinggroups are disclosed in Greene, “Protective Groups In OrganicSynthesis,” (John Wiley & Sons, New York (1981)). Suitable nitrogenprotecting groups comprise acyl groups such as formyl, acetyl,propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,.alpha.-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl,p-toluenesulfonyl and the like; carbamate forming groups such asbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,.alpha.,.alpha.-dimethyl-3,5-dimethoxybenzyloxycarbonyl,benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl,isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl andthe like; and silyl groups such as trimethylsilyl and the like.Preferred suitable nitrogen protecting groups are formyl, acetyl,methyloxycarbonyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl,benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

[0046] As used herein the term “(C₁-C₄)alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 4 carbon atomsand includes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl and the like.

[0047] As used herein the term “(C₁-C₆)alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 6 carbon atomsand includes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0048] As used herein the term “(C₁-C₁₀)alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 10 carbon atomsand includes, but is not limited to methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl,2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl,octyl, 4methyl-3-heptyl and the like.

[0049] As used herein the term “(C₁-C₂₀)alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 20 carbon atomsand includes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl,2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl,n-nonadecyl, n-eicosyl and the like. It is understood that the terms“(C₁-C₄)alkyl”, “(C₁-C₆)alkyl”, and “(C₁-C₁₀)alkyl” are included withinthe definition of “(C₁-C₂₀)alkyl”.

[0050] As used herein, the terms “Me”, “Et”, “Pr”, “iPr”, “Bu” and“t-Bu” refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butylrespectively.

[0051] As used herein, the term “(C₁-C₄)alkoxy” refers to an oxygen atombearing a straight or branched, monovalent, saturated aliphatic chain of1 to 4 carbon atoms and includes, but is not limited to methyoxy,ethyoxy, n-propoxy, isopropoxy, n-butoxy, and the like.

[0052] As used herein the term “(C₁-C₆)alkoxy” refers to an oxygen atombearing a straight or branched, monovalent, saturated aliphatic chain of1 to 6 carbon atoms and includes, but is not limited to methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, n-pentoxy, n-hexoxy, and the like.

[0053] As used herein, the term “(C₁-C₆)alkyl(C₁-C₆)alkoxy” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has a (C₁-C₆)alkoxy group attached to the aliphaticchain.

[0054] As used herein, the terms “Halo”, “Halide” or “Hal” refer to achlorine, bromine, iodine or fluorine atom, unless otherwise specifiedherein.

[0055] As used herein the term “(C₂-C₆)alkenyl” refers to a straight orbranched, monovalent, unsaturated aliphatic chain having from two to sixcarbon atoms. Typical C₂-C₆ alkenyl groups include ethenyl (also knownas vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl,2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, andthe like.

[0056] As used herein, the term “aryl” refers to a monovalentcarbocyclic group containing one or more fused or non-fused phenyl ringsand includes, for example, phenyl, 1- or 2-naphthyl,1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and the like. The term“substituted aryl” refers to an aryl group substituted with one or twomoieties chosen from the group consisting of halogen, hydroxy, cyano,nitro, (C₁-C₆)alkyl, (C₁-C₄)alkoxy, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,(C₁-C₆)alkylaryl, (C₁-C₆)alkoxycarbonyl, protected carboxy,carboxymethyl, hydroxymethyl, amino, aminomethyl, or trifluoromethyl.

[0057] As used herein, the term “(C₁-C₆)alkylaryl” refers to a straightor branched, monovalent, saturated aliphatic chain of 1 to 6 carbonatoms which has an aryl group attached to the aliphatic chain. Includedwithin the term “C₁-C₆ alkylaryl” are the following:

[0058] and the like.

[0059] As used herein, the term “aryl(C₁-C₆)alkyl” refers to an arylgroup which has a straight or branched, monovalent, saturated aliphaticchain of 1 to 6 carbon atoms attached to the aryl group. Included withinthe term “aryl(C₁-C₆)alkyl” are the following:

[0060] and the like.

[0061] As used herein the term “(C₃-C₁₀)cycloalkyl” refers to asaturated hydrocarbon ring structure composed of one or more fused orunfused rings containing from three to ten carbon atoms. Typical C₃-C₁₀cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, adamantanyl, and the like.

[0062] As used herein, the term “C₁-C₆ alkyl(C₃-C₁₀)cycloalkyl” refersto a straight or branched, monovalent, saturated aliphatic chain of 1 to6 carbon atoms which has a (C₃-C₁₀)cycloalkyl attached to the aliphaticchain. Included within the term “C₁-C₆ alkyl(C₃-C₁₀)cycloalkyl” are thefollowing:

[0063] and the like.

[0064] As used herein, the term “(C₁-C₆) alkoxycarbonyl” refers to acarbonyl group having a (C₁-C₆)alkyl group attached to the carbonylcarbon through an oxygen atom. Examples of this group includet-buoxycarbonyl, methoxycarbonyl, and the like.

[0065] As used herein the term “heterocycle” refers to a five- orsix-membered ring, which contains one to four heteroatoms selected fromthe group consisting of oxygen, sulfur, and nitorgen. The remainingatoms of the ring are recognized as carbon by those of skill in the art.Rings may be saturated or unsaturated. Examples of heterocycle groupsinclude thiophenyl, furyl, pyrrolyl, imidazolyl, pyrrazolyl, thiazolyl,thiazolidinyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl,pyridiazinyl, triazinyl, imidazolyl, dihydropyrimidyl,tetrahydropyrimdyl, pyrrolidinyl, piperidinyl, piperazinyl,pyrazolidinyl, pyrimidinyl, imidazolidimyl, morpholinyl, pyranyl,thiomorpholinyl, and the like. The term “substituted heterocycle”represents a heterocycle group substituted with one or two moietieschosen from the group consisting of halogen, hydroxy, cyano, nitro, oxo,aryl, (C₁-C₆)alkyl, (C₁-C₄)alkoxy, C₁-C₆ alkyl(C₃-C₁₀)cycloalkyl,(C₁-C₆)alkylaryl, (C₁-C₆)alkoxycarbonyl, protected carboxy,carboxymethyl, hydroxymethyl, amino, aminomethyl, or trifluoromethyl.Further, the heterocycle group can be optionally fused to one or twoaryl groups to form a benzo-fused group. Examples of substitutedheterocycle include 1,2,3,4-tetrahydrodibenzeofuranyl,2-methylbezylfuranyl, and 3,5 dimethylisoxazolyl, and the like.

[0066] As used herein, the term “(C₁-C₆)alkyl-heterocycle” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms bearing a heterocycle group. Further, as used herein, theterm “(C₁-C₆)alkyl-(substituted)heterocycle” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 6 carbon atomsbearing a substituted heterocycle group.

[0067] As used herein, the term “(C₁-C₆)alkyltetrazole” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms bearing a tetrazole group.

[0068] As used herein, the term “benzo-fused group” refers to a phenylgroup fused to an aromatic radical or a heterocycle group. Includedwithin the term “benzo-fused group” are the following:

[0069] and the like, wherein all substituents are as previously definedhereinabove.

[0070] As used herein, the term “triazole-fused group” refers to atriazole group fused to an aromatic radical or a heterocycle group.Included within the term “triazole-fused group” are the following:

[0071] and the like, wherein all substituents are as previously defined.

[0072] As used herein the term “N,N—C₁-C₆ dialkylamine” refers to anitrogen atom substituted with two straight or branched, monovalent,saturated aliphatic chains of 1 to 6 carbon atoms. Included within theterm “N,N—C₁-C₆ dialkylamine” are —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂,—N(CH₂CH₂CH₂CH₃)₂, and the like.

[0073] As used herein the term “C₁-C₆alkyl-N,N—C₁-C₆dialkylamine” refersto straight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has an N,N—C₁-C₆ dialkylamine attached to thealiphatic chain. Included within the term “C₁-C₆ alkyl-N,N—C₁-C₆dialkylamine” are the following:

[0074] and the like.

[0075] As used herein the term “(C₁-C₆)alkyl-pyrrolidine” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has a pyrrolidine attached to the aliphatic chain.Included within the scope of the term “(C₁-C₆)alkyl-pyrrolidine” are thefollowing:

[0076] and the like.

[0077] As used herein the term “(C₁-C₆)alkyl-piperidine” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has a piperidine attached to the aliphatic chain.Included within the scope of the term “(C₁-C₆)alkyl-piperidine” are thefollowing:

[0078] and the like.

[0079] As used herein the term “(C₁-C₆)alkyl-morpholine” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has a morpholine attached to the aliphatic chain.Included within the scope of the term “C₁-C₆ alkyl-morpholine” are thefollowing:

[0080] and the like.

[0081] The designation “z,900 ” refers to a bond that protrudes forwardout of the plane of the page.

[0082] The designation “z,901 ” refers to a bond that protrudes backwardout of the plane of the page.

[0083] As used herein the term “iGluR₅” refers to the kainate ionotropicglutamate receptor, subtype 5, of the larger class of excitatory aminoacid receptors.

[0084] As used herein the term “migraine” refers a disorder of thenervous system characterized by recurrent attacks of head pain (whichare not caused by a structural brain abnormalitiy such as thoseresulting from tumor or stroke), gasrointestinal disturbances, andpossibly neurological symptoms such as visual distortion. Characteristicheadaches of migraine usually last one day and are commonly accompaniedby nausea, emesis, and photophobia.

[0085] Migraine may represent a “chronic” condition, or an “acute”episode. The term “chronic”, as used herein, means a condition of slowprogress and long continuance. As such, a chronic condition is treatedwhen it is diagnosed and treatment continued throughout the course ofthe disease. Conversely, the term “acute”means an exacerbated event orattack, of short course, followed by a period of remission. Thus, thetreatment of migraine contemplates both acute events and chronicconditions. In an acute event, compound is administered at the onset ofsymptoms and discontinued when the symptoms disappear. As describedabove, a chronic condition is treated throughout the course of thedisease.

[0086] As used herein the term “patient” refers to a mammal, such amouse, gerbil, guinea pig, rat, dog or human. It is understood, however,that the preferred patient is a human.

[0087] The term “iGluR₅ receptor antagonist” or “iGluR₅ antagonist”, asused herein, refers to those excitatory amino acid receptor antagonistswhich bind to, and antagonize the activity of, the iGluR₅ kainatereceptor subtype. As a preferred embodiment, the present inventionfurther provides selective iGluR₅ receptor antagonists. “SelectiveiGluR₅ receptor antagonist” or “selective iGluR₅ antagonist” as usedherein, includes those excitatory amino acid receptor antagonists whichselectively bind to, and antagonize, the iGluR₅ kainate receptorsubtype, relative to the iGluR₂ AMPA receptor subtype. Preferably the“selective iGluR₅ antagonists” for use according to the methods of thepresent invention have a binding affinity at least 10 fold greater foriGluR₅ than for iGluR₂, more preferably at least 100 fold greater. WO98/45270 provides examples of selective iGluR₅ receptor antagonists anddiscloses methods for synthesis.

[0088] As used herein, the terms “treating”, “treatment”, or “to treat”each mean to alleviate symptoms, eliminate the causation of resultantsymptoms either on a temporary or permanent basis, and to prevent, slowthe appearance, or reverse the progression or severity of resultantsymptoms of the named disorder. As such, the methods of this inventionencompass both therapeutic and prophylactic administration.

[0089] As used herein the term “effective amount” refers to the amountor dose of the compound, upon single or multiple dose administration tothe patient, which provides the desired effect in the patient underdiagnosis or treatment. An effective amount can be readily determined bythe attending diagnostician, as one skilled in the art, by the use ofknown techniques and by observing results obtained under analogouscircumstances. In determining the effective amount or dose of compoundadministered, a number of factors are considered by the attendingdiagnostician, including, but not limited to: the species of mammal; itssize, age, and general health; the degree of involvement or the severityof the disease involved; the response of the individual patient; theparticular compound administered; the mode of administration; thebioavailability characteristics of the preparation administered; thedose regimen selected; the use of concomitant medication; and otherrelevant circumstances.

[0090] A typical daily dose will contain from about 0.01 mg/kg to about100 mg/kg of each compound used in the present method of treatment.Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, morepreferably from about 0.1 mg/kg to about 25 mg/kg.

[0091] Oral administration is a preferred route of administering thecompounds employed in the present invention whether administered alone,or as a combination of compounds capable of acting as an iGluR₅ receptorantagonist. Oral administration, however, is not the only route, noreven the only preferred route. Other preferred routes of administrationinclude transdermal, percutaneous, pulmonary, intravenous,intramuscular, intranasal, buccal, sublingual, or intrarectal routes.Where the iGluR₅ receptor antagonist is administered as a combination ofcompounds, one of the compounds may be administered by one route, suchas oral, and the other may be administered by the transdermal,percutaneous, pulmonary, intravenous, intramuscular, intranasal, buccal,sublingual, or intrarectal route, as particular circumstances require.The route of administration inay be varied in any way, limited by thephysical properties of the compounds and the convenience of the patientand the caregiver.

[0092] The compounds employed in the present invention may beadministered as pharmaceutical compositions and, therefore,pharmaceutical compositions incorporating compounds of Formula I areimportant embodiments of the present invention. Such compositions maytake any physical form that is pharmaceutically acceptable, but orallyadministered pharmaceutical compositions are particularly preferred.Such pharmaceutical compositions contain, as an active ingredient, aneffective amount of a compound of Formula I, including thepharmaceutically acceptable salts, prodrugs, and hydrates thereof, whicheffective amount is related to the daily dose of the compound to beadministered. Each dosage unit may contain the daily dose of a givencompound, or may contain a fraction of the daily dose, such as one-halfor one-third of the dose. The amount of each compound to be contained ineach dosage unit depends on the identity of the particular compoundchosen for the therapy, and other factors such as the indication forwhich it is given. The pharmaceutical compositions of the presentinvention may be formulated so as to provide quick, sustained, ordelayed release of the active ingredient after administration to thepatient by employing well known procedures.

[0093] Compositions are preferably formulated in a unit dosage form,each dosage containing from about 1 to about 500 mg of each compoundindividually or in a single unit dosage form, more preferably about 5 toabout 300 mg (for example 25 mg). The term “unit dosage form” refers toa physically discrete unit suitable as unitary dosages for a patient,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical carrier, diluent, or excipient.

[0094] The inert ingredients and manner of formulation of thepharmaceutical compositions are conventional. The usual methods offormulation used in pharmaceutical science may be used here. All of theusual types of compositions may be used, including tablets, chewabletablets, capsules, solutions, parenteral solutions, intranasal sprays orpowders, troches, suppositories, transdermal patches and suspensions. Ingeneral, compositions contain from about 0.5% to about 50% of thecompounds in total, depending on the desired doses and the type ofcomposition to be used. The amount of the compound, however, is bestdefined as the “effective amount”, that is, the amount of each compoundwhich provides the desired dose to the patient in need of suchtreatment. The activity of the compounds employed in the presentinvention do not depend on the nature of the composition, hence, thecompositions are chosen and formulated solely for convenience andeconomy.

[0095] Capsules are prepared by mixing the compound with a suitablediluent and filling the proper amount of the mixture in capsules. Theusual diluents include inert powdered substances such as starches,powdered cellulose especially crystalline and microcrystallinecellulose, sugars such as fructose, mannitol and sucrose, grain flours,and similar edible powders.

[0096] Tablets are prepared by direct compression, by wet granulation,or by dry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

[0097] Tablets are often coated with sugar as a flavor and sealant. Thecompounds may also be formulated as chewable tablets, by using largeamounts of pleasant-tasting substances such as mannitol in theformulation, as is now well-established practice. Instantly dissolvingtablet-like formulations are also now frequently used to assure that thepatient consumes the dosage form, and to avoid the difficulty inswallowing solid objects that bothers some patients.

[0098] A lubricant is often necessary in a tablet formulation to preventthe tablet and punches from sticking in the die. The lubricant is chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils.

[0099] Tablet disintegrators are substances which swell when wetted tobreak up the tablet and release the compound. They include starches,clays, celluloses, algins and gums. More particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used, as well assodium lauryl sulfate.

[0100] Enteric formulations are often used to protect an activeingredient from the strongly acid contents of the stomach. Suchformulations are created by coating a solid dosage form with a film of apolymer which is insoluble in acid environments, and soluble in basicenvironments. Exemplary films are cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate andhydroxypropyl methylcellulose acetate succinate.

[0101] When it is desired to administer the compound as a suppository,the usual bases may be used. Cocoa butter is a traditional suppositorybase, which may be modified by addition of waxes to raise its meltingpoint slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use, also.

[0102] Transdermal patches have become popular recently. Typically theycomprise a resinous composition in which the drugs will dissolve, orpartially dissolve, which is held in contact with the skin by a filmwhich protects the composition. Many patents have appeared in the fieldrecently. Other, more complicated patch compositions are also in use,particularly those having a membrane pierced with innumerable poresthrough which the drugs are pumped by osmotic action.

[0103] The following table provides an illustrative list of formulationssuitable for use with the compounds employed in the present invention.The following is provided only to illustrate the invention and shouldnot be interpreted as limiting the present invention in any way.Formulation 1 Hard gelatin capsules are prepared using the followingingredients: Quantity (mg/capsule) Active Ingredient 250 Starch, dried200 Magnesium stearate 10 Total 460 mg

[0104] The above ingredients are mixed and filled into hard gelatincapsules in 460 mg quantities. Formulation 2 A tablet is prepared usingthe ingredients below: Quantity (mg/tablet) Active Ingredient 250Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid 5Total 665 mg

[0105] The components are blended and compressed to form tablets eachweighing 665 mg. Formulation 3 An aerosol solution is preparedcontaining the following components: Weight % Active Ingredient 0.25Ethanol 29.75 Propellant 22 70.00 (Chlorodifluoromethane) Total 100.00

[0106] The active compound is mixed with ethanol and the mixture addedto a portion of the Propellant 22, cooled to −30° C. and transferred toa filling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container. Formulation 4 Tablets eachcontaining 60 mg of active ingredient are made as follows: ActiveIngredient 60.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mgPolyvinylpyrrolidone 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesiumstearate 0.5 mg Talc 1.0 mg Total 150 mg

[0107] The active ingredient, starch, and cellulose are passed through aNo. 45 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg. Formulation 5 Capsules each containing 80 mg medicamentare made as follows: Active Ingredient 80 mg Starch 59 mgMicrocrystalline cellulose 59 mg Magnesium stearate 2 mg Total 200 mg

[0108] The active ingredient, cellulose, starch, and magnesium stearateare blended, passed through a No. 45 sieve, and filled into hard gelatincapsules in 200 mg quantities. Formulation 6 Suppositories eachcontaining 225 mg of active ingredient may be made as follows: ActiveIngredient 225 mg Saturated fatty acid glycerides 2,000 mg Total 2,225mg

[0109] The active ingredient is passed through a No. 60 mesh U.S. sieveand suspended in the saturated fatty acid glycerides previously meltedusing the minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.Formulation 7 Suspensions each containing 50 mg of medicament per 5 mldose are made as follows: Active Ingredient 50 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v.Color q.v. Purified water to total 5 ml

[0110] The medicament is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with someof the water and added, with stirring. Sufficient water is then added toproduce the required volume. Formulation 8 An intravenous formulationmay be prepared as follows: Active Ingredient 100 mg Mannitol 100 mg 5 NSodium hydroxide 200 ml Purified water to total 5 ml

[0111] It is understood by one of ordinary skill in the art that theprocedures as described above can also be readily applied to a method oftreating neurological disorders or neurodegenerative conditions,particularly pain and migraine, comprising administering to a patient aneffective amount of a compound of Formula I.

[0112] Compounds of Formula I and Formula Ia can be prepared, forexample, by following the procedures set forth in Schemes I and Iabelow. All substituents, unless otherwise indicated, are previouslydefined. The reagents and starting materials are readily available toone of ordinary skill in the art. For example, certain startingmaterials can be prepared by one of ordinary skill in the art followingprocedures disclosed in U.S. Pat. No. 5,356,902 (issued Oct. 18, 1994)and U.S. Pat. No. 5,446,051 (issued Aug. 29, 1995) and U.S. Pat. No.5,670,516 (issued Sep. 23, 1997), the entire contents, all of which areherein incorporated by reference.

[0113] Scheme I provides procedures for the synthesis of compounds ofFormula I and Formula Ia, wherein R¹ represents H, OH, or CO₂H, and R⁴represents H, OH, or CO₂R⁶, respectively.

[0114] In Scheme I, step A, the compound of structure (1) is treatedwith a compound of structure (2) (wherein U represents H, OH, or CO₂R⁶and R⁵, W′, X′, and Y′ are as previously defined), under reductiveamination conditions, to provide the compound of structure (3). Forexample, a solution of ethyl6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate dissolvedin a suitable organic solvent such as 1,2-dichloroethane at roomtemperature, is treated with about 0.5-10.0 equivalents of a compound ofstructure (2) (wherein U represents H, OH, or CO₂R⁶ and R⁵, W′, X′, andY′ are as previously defined) and then the reaction mixture is treatedwith about 0.5-10.0 equivalents of glacial acetic acid and about 2.0equivalents of sodium triacethoxyborohydride. The reaction mixture isstirred under nitrogen for about 10 to 48 hours, quenched with sodiumbicarbonate until pH 8. The compound of structure (3) (wherein Urepresents H, OH, or CO₂R⁶ and R⁵, W′, X′, and Y′ are as previouslydefined) is then isolated using standard procedures. For example, aftertreatment with sodium bicarbonate, the organic layer is separated andthe aqueous phase is extracted with ethyl acetate. The combined organicphases are dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to provide concentrated compound (3). Columnchromatography may then be performed on silica gel with a suitableeluent such as 25% ethyl acetate/hexane to provide the purified compound(3).

[0115] Alternatively, the compound of structure (3) can be prepared byfollowing the sequence of procedures described in Steps B and C. InScheme I, Step B, compound (4) is obtained in a two step procedure.First, reductive amination is performed under conditions describedabove, followed by hydrogenolysis of the resulting benzyl amine toprovide the compound of structure (4). For example, a solution of ethyl6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (compound(1)) dissolved in a suitable organic solvent such as 1,2-dichloroethaneat room temperature, is treated with about 1.1 equivalents of BnNH₂(benzyl amine) and then treated with about 1.5 equivalents of glacialacetic acid and about 1.6 equivalents of sodium triacethoxyborohydride.The reaction mixture is stirred under nitrogen at room temperature forabout 15 hours and then the reaction mixture is treated with sodiumbicarbonate until pH 8, the organic layer separated, and the aqueousphase extracted with ethyl acetate. The combined organic phases aredried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The resulting crude material is used in the next step withoutfurther purification. A mixture of this intermediate dissolved in asuitable organic solvent, such as ethanol, at room temperature istreated with about 0.1 equivalents of 10% palladium on carbon, andhydrogenated at 50 psi at room temperature for about 18 hours. Thecompound of structure (4) is then isolated using standard procedures.For example, the catalyst is removed by filtration through celite andthe solvent evaporated under vacuum to provide the compound of structure(4).

[0116] In Scheme I, Step C, compound (4) is treated with a compound ofstructure (5) (wherein U represents hydrogen, OH, or CO₂R⁶ and R⁵, W′,X′, and Y′ are as defined hereinabove) to provide the compound ofstructure (3). For example, a solution of compound (4) dissolved in asuitable organic solvent such as dimethylsulfoxide, is treated withabout 0.2-4.0 equivalents of compound (5) (wherein U representshydrogen, OH, or CO₂R⁶ and R⁵, W′, X′, and Y′ are as definedhereinabove) and then treated with about 1.0 equivalent of sodiumbicarbonate. The reaction mixture is heated at 120° C. for 20-70 hours.The compound of structure (3) (as previously defined in Step A) is thenisolated using standard procedures. For example, the reaction mixture istreated with ammonium chloride and extract with ethyl acetate, theorganic layer is separated and the aqueous phase is extracted with ethylacetate. The combined organic phases are dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum to provide concentratedcompound (3). Column chromatography may then be performed on silica gelwith a suitable eluent such as 33% ethyl acetate/hexane to provide thepurified compound (3).

[0117] In Scheme I, Step D, compound (3) is concomitantly hydrolyzed anddeprotected under standard conditions well known in the art to providethe compounds of Formula I, wherein R¹, for purposes of this Scheme,represents hydrogen, OH, or CO₂H. For example, compound (3) is treatedwith 6N hydrochloric acid and stirred at 90° C. for 10-24 hours. Themixture is then concentrated under vacuum to provide the compounds ofFormula I, wherein R¹ represents hydrogen, OH, or CO₂H and R², W, X, andY are as previously defined.

[0118] In Scheme I, Step E, the compound of Formula I (wherein forpurposes of the present Scheme R¹ represents hydrogen, OH, or CO₂H andR², W, X, and Y are as previously defined) may be esterified understandard conditions known in the art to provide the compound of FormulaIa, wherein for purposes of the present Scheme R⁴ represents hydrogen,OH, or CO₂R⁶ and R³, R⁵, W′, X′, and Y′ are as previously defined. Forexample, the compound of Formula I is dissolved in a suitable base suchas 2-ethylbutanol, isobutanol, or ethanol, and treated with an excess ofa dehydrating agent, such as thionyl chloride. The reaction mixture isheated at 120° C. for about 2-24 hours. The reaction mixture is thenconcentrated under vacuum to provide the crude compound of Formula Ia(wherein for purposes of the present Scheme R⁴ represents hydrogen, OH,or CO₂R⁶ and R³, R⁵, W′, X′, and Y′ are as previously defined.) Thismaterial may then be precipitated with diethyl ether and filtered toprovide the purified compound of Formula Ia.

[0119] In Scheme I, Step F, the compound of Formula Ia (wherein forpurposes of the present Scheme R⁴ represents hydrogen, OH, or CO₂R⁶ andR³, R⁵, W′, X′, and Y′ are as previously defined) may be hydrolyzedunder standard conditions well known in the art to provide the compoundof Formula I. For example, the compound of Formula Ia is dissolved in asuitable organic solvent such as methanol, and treated with an excess ofa suitable base. Examples of suitable bases include aqueous lithiumhydroxide, sodium hydroxide, potasium hydroxide, and the like withlithium hydroxide being preferred. The reaction is stirred for about10-20 hours. The reaction mixture is then neutralized to pH 6 with 1NHCl and concentrated under vacuum to provide the crude of compound ofFormula I, wherein for purposes of the present Scheme R¹ representshydrogen, OH, or CO₂H and R², W, X, and Y are as previously defined.This material may then be purified by techniques well known in the art,such as cation exchange chromatography eluting with methanol/waterfollowed by 2.0 N ammonia in methanol to provide the purified compoundof Formula I.

[0120] The compounds of Formula I and Formula Ia, wherein R¹ and R⁴represent tetrazole or (C₁-C₄)alkyltetrazole, may be synthesizedaccording to the procedures as described in Scheme Ia.

[0121] In Scheme Ia, step A, following the procedures as described inScheme I, Step A above, the compound of structure (1) is treated with acompound of structure (6) (wherein for the purposes of the presentScheme CN represents a nitrile group, m=0, 1, 2, 3, or 4, and R⁵, W′,X′, and Y′ are as previously defined), under reductive aminationconditions, to provide the compound of structure (7). The compound (7)is then isolated and concentrated under standard conditions, and maythen be purified, all as described in Scheme I, Step A.

[0122] Alternatively, the compound of structure (7) can be prepared byfollowing the sequence of procedures described in Steps B and C. InScheme Ia, Step B, compound (4) is obtained in a two step procedure aspreviously described in Scheme I, Step B above. The compound ofstructure (4) is then isolated using standard procedures, again asdescribed in Scheme I, Step B above.

[0123] In Scheme Ia, Step C, following the procedures as described inScheme I, Step C above, compound (4) is treated with a compound ofstructure (8)(wherein for the purposes of the present Scheme CNrepresents a nitrile group, m=0, 1, 2, 3, or 4, and R⁵, W′, X′, and Y′are as defined hereinabove) to provide the compound of structure (7).The compound of structure (7) is then isolated and concentrated understandard conditions, and may then be purified, all as described inScheme I, Step C.

[0124] Where it is desired that the compound of Formula I or Formula Iacontain a tetrazole or a (C₁-C₄)alkyltetrazole at R¹, compound (7),wherein CN represents a nitrile and m=0, 1, 2, 3, or 4, is treated witha compound of Alk₃SnN₃ (wherein Alk represents an alkyl group such asmethyl, ethyl or butyl) in Scheme Ia, Step D to give the compound ofstructure (9). Compound (9) is then concomitantly hydrolyzed anddeprotected in Step E, to provide the compounds of Formula I, wherein R¹is tetrazole or (C₁-C₄)alkyltetrazole. For example, compound (7) istreated with about 3 to 5 equivalents of azido-tri-n-butyl stannane atabout 70 to 100° C. for about 12 to 48 hours under an atmosphere ofnitrogen to give the compound of structure (9). Compound (9) is thentreated with 1N hydrochloric acid, extracted with ethyl acetate, theorganic layer separated, and the aqueous phase extracted with ethylacetate. The combined organic phases are dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum to provide concentratedcompound (9). Column chromatography may then be performed on silica gelwith a suitable eluent such as 33% ethyl acetate/hexane to provide thepurified compound (9). In Scheme Ia, Step E, Compound (9) is thenconcomitantly hydrolyzed and deprotected under standard conditions wellknown in the art, and as described in Scheme I, Step D above, and theresulting compound of Formula I (wherein R¹ is tetrazole or(C₁-C₄)alkyltetrazole) may then be purified. For example, a solution ofcompound (9) dissolved in 6.0 N hydrochloric acid is heated at 90° C.for 10-24 hours. The reaction mixture is then allowed to cool to roomtemperature and concentrated under vacuum to provide the compound ofFormula I, wherein for the purposes of the present Scheme R¹ istetrazole or (C₁-C₄)alkyltetrazole and R², W, X, and Y are as previouslydefined. This material may then be purified by techniques well known inthe art, such as cation exchange chromatography eluting withmethanol/water followed by 2.0 N ammonia in methanol to provide thepurified compound of Formula I.

[0125] In Scheme Ia, Step F, following the procedures as described inScheme I, Step E, the compound of Formula I (wherein for purposes of thepresent Scheme R¹ represents tetrazole or (C₁-C₄)alkyltetrazole and R²,W, X, and Y are as previously defined) may be esterified under standardconditions known in the art to provide the compound of Formula Ia,wherein for purposes of the present Scheme R⁴ represents tetrazole or(C₁-C₄)alkyltetrazole and R³, R⁵, W′, X′, and Y′ are as previouslydefined. For example, the compound of Formula I is dissolved in asuitable base such as 2-ethylbutanol, isobutanol, or ethanol, andtreated with an excess of a dehydrating agent, such as thionyl chloride.The reaction mixture is heated at 120° C. for about 2-24 hours. Thereaction mixture is then concentrated under vacuum to provide the crudecompound of Formula Ia (wherein for purposes of the present Scheme R⁴represents tetrazole or (C₁-C₄)alkyltetrazole and R³, R⁵, W′, X′, and Y′are as previously defined.) This material may then be precipitated withdiethyl ether and filtered to provide the purified compound of FormulaIa.

[0126] In Scheme Ia, Step G, the compound of Formula Ia (wherein forpurposes of the present Scheme R⁴ tetrazole or (C₁-C₄)alkyltetrazole andR³, R⁵, W′, X′, and Y′ are as previously defined) may be hydrolyzedunder standard conditions well known in the art, and as previouslydescribed in Scheme I, Step F above to provide the compound of FormulaI. This material may then be purified by techniques well known in theart, such as cation exchange chromatography eluting with methanol/waterfollowed by 2.0 N ammonia in methanol to provide the purified compoundof Formula I, wherein R⁴ tetrazole or (C₁-C₄)alkyltetrazole and R³, R⁵,W′, X′, and Y′ are as previously defined.

[0127] The Formula I compounds of the present invention may bechemically synthesized from a common intermediate, a6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate. Thisintermediate, in turn, may be synthesized from a6-oxo-decahydroisoquinoline-3-carboxylic acid, the synthesis of which isdescribed in U.S. Pat. Nos. 4,902,695, 5,446,051, and 5,356,902, thecontents of which are all herein incorporated by reference. A route forthe synthesis of the6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylateintermediate, useful for the synthesis of the compounds of the presentinvention, is shown in Scheme II below.

[0128] In Scheme II, Step A,6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylic acid (Pg is as definedhereinabove) is esterified by reaction with a compound of formula R³—Br(where R³ is as herein defined above) to provide the6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylate intermediate ofcompound (1). For example6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid isdissolved in acetonitrile and treated with tiethylamine and bromoethane.The reaction is heated at 50° C. for about 3 hours, cooled andpartitioned between 50:50 ethyl acetate/heptane and 1N HCL. The organicphase is isolated and washed 3 times with water, saturated sodiumbicarbonate, brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to provide Ethyl6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate, a compoundof structure (1). This crude material may then be purified understandard conditions well known in the art. For example, the crudematerial is dissolved in 10% ethyl acetatelheptane and applied to a plugof silica gel (10 g in 10% ethyl acetate/heptane). The plug is elutedwith, 10% ethyl acetate/heptane, 15% ethyl acetate/heptane, and 25%ethyl acetate/heptane. The eluents are combined and concentrated undervacuum to provide the purified compound of structure (1).

[0129] The following preparations and examples further illustrate theinvention and represent typical synthesis of the compounds of Formula Ias described generally above. The reagents and starting materials arereadily available to one of ordinary skill in the art. As used herein,the following terms have the meanings indicated: “i.v.” refers tointravenously; “p.o.” refers to orally; “i.p.” refers tointraperitoneally; “eq” or “equiv.” refers to equivalents; “g” refers tograms; “mg” refers to milligrams; “L” refers to liters; “mL” refers tomilliliters; “μL” refers to microliters; “mol” refers to moles; “mmol”refers to millimoles; “psi” refers to pounds per square inch; “mm Hg”refers to millimeters of mercury; “min” refers to minutes; “h” or “hr”refers to hours; “° C.” refers to degrees Celsius; “TLC” refers to thinlayer chromatography; “HPLC” refers to high performance liquidchromatography; “R_(f)” refers to retention factor; “R_(t)” refers toretention time; “δ” refers to part per million down-field fromtetramethylsilane; “THF” refers to tetrahydrofuran; “DMF” refers toN,N-dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “aq” refersto aqueous; “EtOAc” refers to ethyl acetate; “iPrOAc” refers toisopropyl acetate; “MeOH” refers to methanol; “MTBE” refers totert-butyl methyl ether; “PPh₃” refers to triphenylphosphine; “DEAD”refers to diethyl azodicarboxylate; “RT” refers to room temperature;“Pd—C” refers to palladium over carbon; NaBH(OAc)₃ refers to sodiumtriacetoxyborohydride; “Bn” refers to benzyl; “BnNH₂” refers to benzylamine; H₂ refers to hydrogen; “K_(i)” refers to the dissociationconstant of an enzyme-antagonist complex and serves as an index ofligand binding; and “ID₅₀” and “ID₁₀₀” refer to doses of an administeredtherapeutic agent which produce, respectively, a 50% and 100% reductionin a physiological response.

[0130] Preparation 1

[0131] Ethyl (3S, 4aR, 6S, 8aR)6-amino-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinol-3-carboxylate.

[0132] A. Ethyl (3S, 4aR, 6S, 8aR)6-benzylamino-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.

[0133] To a room temperature solution of ethyl6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate (4 g, 14.1mmol), benzylamine (1.71 g, 15.9 mmol), and acetic acid (1.27 g, 21.2mmol) in 1,2-dichloroethane (20 ml), sodium triacetoxyborohydride (5 g,23.3 mmol) was added. The mixture was stirred under an atmosphere ofnitrogen for 15 hours at room temperature. The reaction was quenched byadding aqueous saturated sodium bicarbonate, and extracted withdichloromethane three times. The organic layer was dried over sodiumsulfate and evaporated to give 7 g of the title compound. The crudematerial was used in next step without further purification.

[0134] Ion Electrospray Mass Spectrum M+1:375

[0135] B. Ethyl (3S, 4aR, 6S, 8aR)6-amino-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.

[0136] A mixture of the intermediate from step A above (7g, 18.7 mmol)and 700 mg of 10% palladium on carbon in 30 mL of ethanol washydrogenated at 50 psi for 18 hours at room temperature. The catalystwas removed by filtration through celite and the solvent was evaporatedunder reduced pressure to afford 4 g of the title compound.(Quantitative yield)

[0137] 1H-NMR (CDCl3, 200.15 MHz): 4.57 (t, J=5.4 Hz, 1H); 4.23-4.12 (m,2H); 3.69 (s, 3H); 3.69-3.55 (m, 1H); 3.36-3.30 (m, 1H); 3.02 (s, 1H);2.26-2.02 (m, 3H); 1.77-1.57 (m, 7H); 1.43-1.37 (m, 3H); 1.25 (t, J=7.0Hz, 3H).

[0138] Ion Electrospray Mass Spectrum M+1:285

EXAMPLE 1

[0139] Preparation of (3S, 4aR, 6S, 8aR)6-(3-chloro-2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid dihydrochloride

[0140] A. Ethyl (3S, 4aR, 6S, 8aR)6-(3-chloro-2-cyano-phenylamino)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.

[0141] To a mixture of ethyl 6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (142 mg, 0.5 mmol),2-amino-6-chloro-benzonitrile (760 mg, 5.0 mmol), and glacial aceticacid (0.36 mL, 6.0 mmol) in 1,2-dichloroethane (5 mL), was added 5 g ofof 4A molecular sieves (excess of dehydrating agent just to forcereaction to completion) and stirred at room temperature overnight undernitrogen. Then, sodium triacethoxyborohydride solid (211 mg, 1.0 mmol)was added and the reaction mixture stirred under nitrogen at roomtemperature for two days. The reaction mixture was then filtered throughcelite and sodium bicarbonate was added until pH 8, followed by additionof ethyl acetate. The phases were separated and the aqueous phase washedtwice with ethyl acetate. The combined organic phases were dried withanhydrous sodium sulfate and concentrate in vacuo. Flash chromatography(silica gel, hexane-ethyl acetate 3:1) afforded 120 mg (29% yield) ofthe title compound.

[0142] Ion Electrospray Mass Spectrum M+1:420

[0143] B. Ethyl-(3S, 4aR, 6S, 8aR)6-(3-chloro-2-(1(2)H-tetrazol-5-yl)-phenylamino)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[0144] To the product from Example 1A (100 mg, 0.238 mmol), neatazidotributyltin (0.13 mL, 0.477 mmol) was added and heated at 100° C.overnight. 1N HCl (5 mL) was added, followed by extraction with ethylacetate (2×), dried with anhydrous sodium sulfate, and concentrated invacuo. Flash chromatography (silica gel, hexane-ethyl acetate-aceticacid 2:1:2%) afforded 62 mg (56% yield) of the title compound.

[0145] Ion Electrospray Mass Spectrum M+1:463.

[0146] C. (3S, 4aR, 6S, 8aR)6-(3-chloro-2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid dihydrochloride

[0147] The product from Example 1B (50 mg, 0.108 mmol)was treated with a6N HCl under reflux overnight. The solution was concentrated in vacuo toafford 34 mg (83% yield) of the title compound.

[0148] Ion Electrospray Mass Spectrum M+1:377

EXAMPLE 2

[0149] Preparation of 2-ethyl-butyl (3S, 4aR, 6S, 8aR)6-(3-chloro-2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatedihydroiodide

[0150] 2-ethyl-butyl (3S, 4aR, 6S, 8aR)6-(3-chloro-2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatedihydroiodide is prepared essentially as described for Example 5 herein.

EXAMPLE 3

[0151] Preparation of (3S, 4aR, 6S, 8aR)6-(2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid dihydrochloride

[0152] A. Ethyl (3S, 4aR, 6S, 8aR)6-(2-cyano-phenylamino)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[0153] To a mixture of of ethyl6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (537 mg,1.9 mmol), 2-amino-6-chloro-benzonitrile (118 mg, 1.0 mmol), and glacialacetic acid (0.36 mL, 6.0 mmol) in 1,2-dichloroethane (5 mL), sodiumtriacethoxyborohydride solid (590 mg, 2.8 mmol) was added and thereaction mixture stirred under nitrogen at room temperature for 24hours. Sodium bicarbonate was added until pH 8, followed by addition ofethyl acetate. The phases were separated and the aqueous phase washedtwice with ethyl acetate. The combined organic phases were dried withanhydrous sodium sulfate and concentrated in vacuo. Flash chromatography(silica gel, hexane-ethyl acetate 3:1) afforded 123 mg (32% yield) ofthe title compound.

[0154] Ion Electrospray Mass Spectrum M+1: 384

[0155] B. Ethyl (3S, 4aR, 6S, 8aR)6-(2-(1(2)H-tetrazol-5-yl)-phenylamino)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[0156] Following the procedures from Example 1B, and using the productfrom Example 3A (120 mg, 0.31 mmol) neat azidotributyltin (0.17 mL, 0.62mmol) was added Flash chromatography (silica gel, hexane-ethylacetate-AcOH 2:1:2%) afforded 80 mg (60% yield) of the title compound.

[0157] Ion Electrospray Mass Spectrum M+1: 429

[0158] C. (3S, 4aR, 6S, 8aR)6-(2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid dihydrochloride

[0159] The product from Example 3B (70 mg, 0.164 mmol) was treatedfollowing the procedures from Example 1C and afforded 49 mg (87% yield)of the title compound.

[0160] Mass Spectrum (Fast Atom Bombardement)M+1: 343

EXAMPLE 4

[0161] Preparation of isobutyl (3S, 4aR, 6S, 8aR))6-(2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatedihydrochloride

[0162] A. Isobutyl alcohol (HCl)

[0163] Anhydrous isobutyl alcohol (20 mL) was bubble with HCl (g) forabout 5 to 10 min.

[0164] B. Isobutyl-(3S, 4aR, 6S, 8aR)6-(2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatedihydrochloride

[0165] Compound from Example 4A was added to compound from Example 3C(2.0 g, 4.82 mmol) and reflux overnight to afford 2.11 g (93% yield) ofthe title compound.

[0166] Ion Electrospray Mass Spectrum M+1: 472

EXAMPLE 5

[0167] Preparation of 2-ethyl-butyl (3S, 4aR, 6S, 8aR)6-(2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatedihydrochloride

[0168] A. 2-Ethyl-1-butanol(HCl)

[0169] Anhydrous 2-ethyl-1-butanol (20 mL) was bubble with HCl (g) forabout 10 to 15 min.

[0170] B. 2-Ethylbutyl (3S, 4aR, 6S, 8aR)6-(2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatedihydrochloride

[0171] Compound from Example 5A was added to compound from Example 3B(2.0 g, 4.82 mmol) and refluxed overnight to afford 2.09 g (87% yield)of the title compound.

[0172] Ion Electrospray Mass Spectrum M+1: 500

EXAMPLE 6

[0173] Preparation of (3S, 4aR, 6S, 8aR)6-(2-carboxyphenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

[0174] A. Ethyl (3S, 4aR, 6S, 8aR)6-(2-ethoxycarbonylphenylamino)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[0175] Following the procedure from Example 3A, and using ethyl6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (537 mg,1.9 mmol), 2-aminobenzoate (165 mg, 1.0 mmol), glacial acetic acid (0.36mL, 6.0 mmol), and sodium triacethoxyborohydride (590 mg, 2.8 mmol),flash chromatography (silica gel, hexane-ethyl acetate 3:1) afforded 181mg (42% yield) of the title compound.

[0176] Ion Electrospray Mass Spectrum M+1: 433

[0177] B. (3S, 4aR, 6S, 8aR)6-(2-carboxyphenylamiino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid dihydrochloride

[0178] Following the procedures from Example 1C, the product fromExample 6A (100 mg, 0.232 mmol) afforded 95 mg of a white solid.

[0179] C. (3S, 4aR, 6S, 8aR)6-(2-carboxyphenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

[0180] The product from Example 6B (95 mg, 0.24 mmol) was dissolved inwater and Dowex resin (2.0 g) was added and stirred for 1 hour. Waterwas washed away by filtration and the resin washed with 50 mL 1:1THF/water, then washed with water (50 mL). The resin was collected and a10% solution of Pyridine-water was added. This was stirred for 2 hours,filtered, and the filtrate collected. The resin was washed with water(10 mL) and the combined pyridine-water filtrate was concentrate invacuo to afford 51 mg (67% yield) of the title compound as a whitesolid.

[0181] Mass Spectrum (Fast Atom Bombardement)M+1: 319

[0182] Analysis calculated for C₁₇H₂₂N₂O₄2H₂O: %C, 57.61; %H, 7.39; %N,7.90. Found %C, 57.82; %H, 7.41; %N, 7.83.

EXAMPLE 7

[0183] Preparation of Ethyl (3S, 4aR, 6S, 8aR)6-(2-ethoxycarbonylphenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatedihydrochloride

[0184] A. Ethanol (HCl)

[0185] Anhydrous ethanol (20 mL) was bubble with HCl (g) for about 5 to10 min.

[0186] B. (3S, 4aR, 6S, 8aR)6-(2-ethoxycarbonylphenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ethyl ester dihydrochloride

[0187] Compound from Example 7A was added to compound from Example 6B(2.0 g, 5.1 mmol) and refluxed overnight to afford (2.1 g, 93% yield) ofthe title compound.

[0188] Ion Electrospray Mass Spectrum M+1: 448

EXAMPLE 8

[0189] Preparation of (3S, 4aR, 6S, 8aR)6-(3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenylamino)1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acidditrifluoroacetate

[0190] A. Ethyl (3S, 4aR, 6S, 8aR)6-(3-fluoro-2-cyano-phenylamino)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[0191] Following the procedures from Example 3A, and using 5.38 g (19.0mmol) of ethyl6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate, 1.36 g(10.0 mmol) of 2-amino-6-fluorobenzonitrile, 3.6 mL (60 mmol) of glacialacetic acid, 5.7 g (27.0 mmol) of sodium triacetoxyborohydride, flashchromatography (silica gel, hexane-ethyl acetate 3:1) afforded 50 mg (1%yield) of the title compound.

[0192] Ion Electrospray Mass Spectrum M+1: 404

[0193] B. (3S, 4aR, 6S, 8aR)6-(3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenylamino)1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acidditrifluoroacetate

[0194] To the product from Example 8A (50 mg, 0.124 mmol) was added neatazidotributyltin (0.068 mL, 0,248 mmol) and the reaction heated at 100°C. overnight. A 6N HCl solution was added and heated at the sametemperature for 24 hours, followed by extraction with ethyl ether (2×).The aqueous phase was concentrate in vacuo to afford the title compoundas dihydrochloride. This crude material was purified by HPLC (using aseluent a gradient of acetonitrile-1% TFA and water) to afford 15 mg (3%)of the title compound

EXAMPLE 9

[0195] Preparation of (3S, 4aR, 6S, 8aR)6-(5-phenyl-2-(1(2)H-tetrazol-5-yl)-phenylamino)1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic aciddihydrochloride

[0196] A. 3-Fluoro-biphenyl-4-carbonitrile

[0197] To a solution of 4-bromo-2-fluorobenzonitrile (1.12 g, 5.6 mmol)in 1,2-dimethoxyethane (10 mL) were added Phenyl boronic acid (750 mg,6.16 mmol), tetrakis(triphenylphosphine)palladium (0) (194 mg, 0.17mmol) and Cesium fluoride (1.8 g, 12.3 mmol). The mixture of reactionwas stirred at 100° C. under nitrogen for 3 h. Then, the mixture iscooled and filter through celite. Then added ethyl acetate and water andextracted (3×). The crude was purified by chromatography (silica gel,hexane-ethyl acetate 10:1) affordind 818 mg (74% yield)n of the titlecompound.

[0198] B. Ethyl (3S, 4aR, 6S, 8aR)6-(2-cyano-5-phenyl-phenylamino)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[0199] To a mixture of the intermediate from preparation 1 (426 mg, 1.5mmol) and the product from 9A (100 mg, 0.5 mmol) in DMSO (2 mL) wasadded powdered NaHCO₃ (100 mg, 1.0 mmol) and the reaction mixture heatedat 120° C. for 70 h. Then, a saturated solution of NH₄Cl was added andextracted with ethyl acetate (2×), dried, and concentrated in vacuo.Flash chromatography (silica gel, hexane-ethyl acetate 2:1) afforded 125mg (55% yield) of the title product.

[0200] Ion Electrospray Mass Spectrum M+1: 462

[0201] C. Ethyl (3S, 4aR, 6S, 8aR)6-(4-phenyl-2-(1(2)H-tetrazol-5-yl)-phenylamino)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[0202] Following the procedures from Example 1B, and using the productfrom Example 9B(125 mg, 0.27 mmol) and neat azidotributyltin (150 mL,0.54 mmol), flash chromatography (silica gel, hexane-ethylacetate-acetic acid 2:1:2%) afforded 95 mg (70% yield) of the titlecompound.

[0203] Ion Electrospray Mass Spectrum M+1:505

[0204] D. (3S, 4aR, 6S, 8aR)6-(5-phenyl-2-(1(2)H-tetrazol-5-yl)-phenylamino)1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic aciddihydrochloride

[0205] Following the procedures from Example 1C, and using the productfrom Example 9C (90 mg, 0.18 mmol) afforded 60 mg (75% yield) of thetitle compound

[0206] Ion Electrospray Mass Spectrum M+1:419

EXAMPLE 10

[0207] Preparation of (3S, 4aR, 6S, 8aR)6-(2-Carboxy-4-fluoro-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid dihydrochloride

[0208] A. Ethyl (3S, 4aR, 6S, 8aR)6-(2-ethoxycarbonyl-4-fluoro-phenylamino)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[0209] Following the procedures from Example 1A, and using ethyl6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (537 mg,1.9 mmol), 2-amino-5-fluoro-benzoic acid ethyl ester (183 mg, 1.0 mmol),glacial acetic acid (0.36 mL, 6.0 mmol), and sodiumtriacethoxyborohydride (590 mg, 2.8 mmol), flash chromatography (silicagel, hexane-ethyl acetate 3:1) afforded 95 mg (22% yield) of the titlecompound.

[0210] Ion Electrospray Mass Spectrum M+1: 431

[0211] B. (3S, 4aR, 6S, 8aR)6-(2-carboxy-4-fluoro-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid dihydrochloride

[0212] Following the procedures from Example 1C, and using the productfrom Example 10A (90 mg, 0.21 mmol), 45 mg (50% yield) of the titlecompound was afforded.

[0213] Ion Electrospray Mass Spectrum M+1: 364

EXAMPLE 11

[0214] Preparation of (3S, 4aR, 6S, 8aR)6-(5-methyl-2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ditrifluoroacetate

[0215] A. Ethyl (3S, 4aR, 6S, 8aR)6-(2-cyano-5-methyl-phenylamino)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[0216] Following the procedures from Example 3A, and using 1.076 g (3.8mmol) of ethyl6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate, 1.36 g(10.0 mmol) of 2-amino-5-methylbenzonitrile, 0.67 mL (12 mmol) ofglacial acetic acid, and 1.14 g (5.4 mmol) of sodiumtriacetoxyborohydride, flash chromatography (silica gel, hexane-ethylacetate 3:1) afforded 80 mg (10% yield) of the title compound.

[0217] Ion Electrospray Mass Spectrum M+1: 416

[0218] B. (3S, 4aR, 6S, 8aR)6-(5-methyl-2-(1(2)H-tetrazol-5-yl)-phenylamino)1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acidditrifluoroacetate

[0219] Following the procedures from Example 8B, and using the productfrom Example 11A (80 mg, 0.193 mmol) and azidotributyltin (0.105 mL,0,385 mmol), 10 mg (1%) of the title compound was afforded.

[0220] Ion Electrospray Mass Spectrum M+1: 357

EXAMPLE 12

[0221] Preparation of (3S, 4aR, 6S, 8aR)6-(3-methyl-2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid ditrifluoroacetate

[0222] A. Ethyl (3S, 4aR, 6S, 8aR)6-(2-cyano-3-methyl-phenylamino)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[0223] Following the procedures from Example 3A, and using 1.076 g (3.8mmol) of ethyl6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate, 1.36 g(10.0 mmol) of 2-amino-5-methylbenzonitrile, 0.67 mL (12 mmol) ofglacial acetic acid, and 1.14 g (5.4 mmol) of sodiumtriacetoxyborohydride, flash chromatography (silica gel, hexane-ethylacetate 3:1) afforded 105 mg (13% yield) of the title compound.

[0224] Ion Electrospray Mass Spectrum M+1: 416

[0225] B. (3S, 4aR, 6S, 8aR)6-(3-methyl-2-(1(2)H-tetrazol-5-yl)-phenylamino)1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid dichlorohydrate

[0226] Following the procedures from Example 8B, and using the productfrom Example 12A (100 mg, 0.241 mmol) and azidotributyltin (0.1132 mL,0,482 mmol), 8 mg (1%) of the title compound was afforded.

[0227] Ion Electrospray Mass Spectrum M+1: 357

EXAMPLE 13

[0228] Preparation of (3S, 4aR, 6S, 8aR)6-(3-carboxy-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid dichlorohydride

[0229] A. Ethyl (3S, 4aR, 6S, 8aR)6-(3-ethoxycarbonylphenylamino)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

[0230] Following the procedures from Example 1A, and using ethyl6-oxo-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate (11.4 g,40.28 mmol), 3-aminobenzoic acid ethyl ester (3.5 g, 21.2 mmol), glacialacetic acid (5.0 mL, 84.0 mmol), and sodium triacethoxyborohydride(12.58 g, 59.36 mmol) flash chromatography (silica gel, hexane-ethylacetate 3:1) afforded 8.35 g (92% yield) of the title compound.

[0231] Ion Electrospray Mass Spectrum M+1: 433

[0232] B. (3S, 4aR, 6S, 8aR)6-(3-carboxy-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid dichlorohydride

[0233] Following the procedures from Example 1C, and using the compoundfrom Example 13A (2.7 g, 6.25 mmol) afforded 2.4 g (98% yield) of thetitle compound

[0234] Ion Electrospray Mass Spectrum M+1: 319

[0235] Analysis calculated for C₁₇H₂₄Cl₂N₂O₄H₂O: %C, 49.89; %H, 6.40;%N, 6.84. Found %C, 50.03; %H, 6.28; %N, 6.79.

EXAMPLE 14

[0236] Preparation of Ethyl (3S, 4aR, 6S, 8aR)6-(3-ethoxycarbonyl-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid, dihydrochloride

[0237] The compound from Example 13 (2.3 g, 5.88 mmol) was treated withethanol saturated with HCl and refluxed overnight. Concentration invacuo afforded 2.37 g (90% yield) of the title compound

[0238] Ion Electrospray Mass Spectrum M+1: 375

EXAMPLE 15

[0239] To establish that the iGluR₅ receptor subtype is mediating apharmacological response in a neurological disease or disorder, thebinding affinity of the panel compounds to the iGluR₅ receptor is firstmeasured using standard methods. For example, the activity of compoundsacting at the iGluR₅ receptor can be determined by radiolabelled ligandbinding studies at the cloned and expressed human iGluR₅ receptor(Korczak et al., 1994, Recept. Channels 3; 41-49), and by whole cellvoltage clamp electrophysiological recordings of currents in acutelyisolated rat dorsal root ganglion neurons (Bleakman et al., 1996, Mol.Pharmacol. 49; 581-585). The selectivity of compounds acting at theiGluR₅ receptor subtype can then be determined by comparing antagonistactivity at the iGluR₅ receptor with antagonist activity at other AMPAand kainate receptors. Methods useful for such comparison studiesinclude: receptor-ligand binding studies and whole-cell voltage clampelectrophysiological recordings of functional activity at human GluR₁,GluR₂,GluR₃ and GluR₄ receptors (Fletcher et al., 1995, Recept. Channels3; 21-31); receptor-ligand binding studies and whole-cell voltage clampelectrophysiological recordings of functional activity at human GluR₆receptors (Hoo et al., Recept. Channels 2;327-338); and whole-cellvoltage clamp electrophysiological recordings of functional activity atAMPA receptors in acutely isolated cerebellar Purkinje neurons (Bleakmanet al., 1996, Mol. Pharmacol. 49; 581-585) and other tissues expressingAMPA receptors (Fletcher and Lodge, 1996, Pharmacol. Ther. 70; 65-89).

[0240] iGluR₅ antagonist binding affinity profiles

[0241] Cell lines (HEK293 cells) stably transfected with human iGluRreceptors are employed. Displacement of ³[H] AMPA by increasingconcentrations of antagonist is measured on iGluR₁, iGluR₂, iGluR₃, andiGluR₄ expressing cells, while displacement of ³[H] kainate (KA) ismeasured on iGluR₅, iGluR6, iGluR₇, and KA2-expressing cells. Estimatedantagonist binding activity (K_(i)) in μM, for example, is determinedfor Compounds of Formula I. As an indicia of selectivity, the ratio ofbinding affinity to the iGluR₂ AMPA receptor subtype, versus the bindingaffinity to iGluR₅ kainate receptor subtype (K_(i) at iGluR₂/K_(i) atiGluR5) is also determined. The iGluR5 receptor antagonist compounds, asprovided by the present invention, provide a K_(i) at the iGluR5receptor subtype of less than 5000 μM , preferably less than 500 μM ,even more preferably less than 50 μM, and most preferably less than 5μM. The preferred selective iGluR5 receptor antagonists compounds, asprovided by the present invention, display a greater binding affinity(lower K_(i)) for iGluR₅ than that for iGluR₂, preferably at least 10fold greater for iGluR₅ than that for iGluR₂, and even more preferablyat least 100 fold, and most preferably at least 1000 fold. than that foriGluR₂.

EXAMPLE 16

[0242] The following animal model may be employed to determine theability of each of the compounds of Formula I to inhibit proteinextravasation, an exemplary functional assay of the neuronal mechanismof migraine.

[0243] Animal Model of Dural Protein Extravasation

[0244] Harlan Sprague-Dawley rats (225-325 g) or guinea pigs fromCharles River Laboratories (225-325 g) are anesthetized with sodiumpentobarbital intraperitoneally (65 mg/kg or 45 mg/kg respectively) andplaced in a stereotaxic frame (David Kopf Instruments) with the incisorbar set at −3.5 mm for rats or −4.0 mm for guinea pigs. Following amidline sagital scalp incision, two pairs of bilateral holes are drilledthrough the skull (6 mm posterially, 2.0 and 4.0 mm laterally in rats; 4mm posteriorly and 3.2 and 5.2 mm laterally in guinea pigs, allcoordinates referenced to bregma). Pairs of stainless steel stimulatingelectrodes, insulated except at the tips (Rhodes Medical Systems, Inc.),are lowered through the holes in both hemispheres to a depth of 9 mm(rats) or 10.5 mm (guinea pigs) from dura.

[0245] The femoral vein is exposed and a dose of the test compound isinjected intravenously (i.v.) at a dosing volume of 1 ml/Kg or, in thealternative, test compound is administered orally (p.o) via gavage at avolume of 2.0 ml/Kg. Approximately 7 minutes post i.v. injection, a 50mg/Kg dose of Evans Blue, a fluorescent dye, is also injectedintravenously. The Evans Blue complexes with proteins in the blood andfunctions as a marker for protein extravasation. Exactly 10 minutespost-injection of the test compound, the left trigeminal ganglion isstimulated for 3 minutes at a current intensity of 1.0 mA (5 Hz, 4 msecduration) with a Model 273 potentiostat/galvanostat (EG&G PrincetonApplied Research).

[0246] Fifteen minutes following stimulation, the animals are euthanizedby exsanguination with 20 mL of saline. The top of the skull is removedto facilitate the collection of the dural membranes. The membranesamples are removed from both hemispheres, rinsed with water, and spreadflat on microscopic slides. Once dried, the tissues are coverslippedwith a 70% glycerol/water solution.

[0247] A fluorescence microscope (Zeiss) equipped with a gratingmonchromator and a spectrophotometer is used to quantify the amount ofEvans Blue dye in each sample. An excitation wavelength of approximately535 nm is utilized and the emission intensity at 600 nm is determined.The microscope is equipped with a motorized stage and also interfacedwith a personal computer. This facilitates the computer-controlledmovement of the stage with fluorescence measurements at 25 points (500mm steps) on each dural sample. The mean and standard deviation of themeasurements are determined by the computer.

[0248] The extravasation induced by the electrical stimulation of thetrigeminal ganglion has an ipsilateral effect (i.e. occurs only on theside of the dura in which the trigeminal ganglion was stimulated). Thisallows the other (unstimulated) half of the dura to be used as acontrol. The ratio (“extravasation ratio”) of the amount ofextravasation in the dura from the stimulated side, over the amount ofextravasation in the unstimulated side, is calculated. Control animalsdosed with only with saline, yield an extravasation ratio ofapproximately 2.0 in rats and approximately 1.8 in guinea pigs. Incontrast, a compound which completely prevents the extravasation in thedura from the stimulated side would yield a ratio of approximately 1.0.

[0249] Dose-response curves are generated for each of the compounds ofFormula I and the dose that inhibits the extravasation by 50% (ID₅₀) or100% (ID₁₀₀) is approximated.

EXAMPLE 17

[0250] To demonstrate the utility of compounds of the present inventionto treat pain or provide analgesic effects, several well known animalmodels may be employed. For example, international application WO98/45270 describes the well known Formalin Test, which is describedbelow:

[0251] Formalin Test

[0252] For example, male Sprague-Dawley rats (200-250 g; Charles River,Portage, Mich.) are housed in group cages and maintained in a constanttemperature and a 12 hour light/12 hour dark cycle 4-7 days beforestudies are performed. Animals have free access to food and water at alltimes prior to the day of the experiment.

[0253] Drugs or vehicles are administered intraperitoneally (i.p.) ororally (p.o.) by gavage in a volume of about 1 ml/kg. The test isperformed in custom made Plexiglas® boxes about 25×25×20 cm in size(according to Shibata et al., Pain 38;347-352, 1989, Wheeler-Aceto etal., Pain, 40; 229-238, 1990). A mirror placed at the back of the cageallows the unhindered observation of the formalin injected paw. Rats areacclimated individually in the cubicles at least 1 hour prior to theexperiment. All testing is conducted between, for example, 08:00 and14:00 h and the testing room temperature is maintained at about 21-23°C.

[0254] Test compounds are administered about 30 minutes prior to theformalin injection. Formalin (50 micoliters of a 5% solution in saline)is injected subcutaneously into the dorsal lateral surface of the righthind paw with a 27 gauge needle. Observation is started immediatelyafter the formalin injection. Formalin-induced pain is quantified byrecording, for example, in 5 minute intervals, the number of formalininjected pawlicking events and the number of seconds each licking eventlasts. These recordings are made for about 50 minutes after the formalininjection.

[0255] Several different scoring parameters have been reported for theformalin test. The total time spent licking and biting the injected pawis demonstrated to be most relevant (Coderre et al., Eur. J. Neurosci.6; 1328-1334, 1993; Abbott et al., Pain, 60; 91-102, 1995) and may bechosen for the testing score. The early phase score is the sum of timespent licking, in seconds, from time 0 to 5 minutes. The late phase isscored in 5 minute blocks from 15 minutes to 40 minutes and is expressedaccordingly or also by adding the total number of seconds spent lickingfrom minute 15 to minute 40 of the observation period.

[0256] Data may be presented as means with standard errors of means(±SEM). Data may also be evaluated by one-way analysis of variance(ANOVA) and the appropriate contrasts analyzed by Dunnett “t” test fortwo sided comparisons. Differences are considered to be significant if,for example, the P-value is less than 0.05. Statistics may be determinedat the 5 minute time point and at 5 minute intervals between 15 and 40minutes. Where data are expressed as total amount of time spent lickingin the late phase, statistics may be performed on the total time spentlicking as well and may be indicated accordingly.

[0257] In addition to the Formalin Test, the well known Mouse WrithingTest, essentially as described in published International Application WO00/028980, may also be employed to demonstrate the analgesic propertiesof compounds of the present invention.

[0258] Mouse Writhing Test

[0259] An accepted procedure for detecting and comparing the analgesicactivity of different classes of analgesic drugs, for which there is agood correlation with human analgesic activity, is the prevention ofacetic acid-induced writhing in mice. Mice are orally administeredvarious doses of a test compound or placebo prior to testing. The miceare then injected intraperitoneally with acetic acid (0.55% solution, 10mL/kg) five minutes prior to a designated observation period. Inhibitionof writhing behavior is demonstrative of analgesic activity. Haubrich etal., “Pharmacology of pravadoline: a new analgesic agent”, The Journalof Pharmacology and Experimental Therapeutics, 255 (1990) 511-522. Forscoring purposes “writhe” is indicated by whole body stretching orcontracting of the abdomen during an observation period beginning aboutfive minutes after receiving the acetic acid.

[0260] ED₅₀ values, and their standard error of means (SEM), aredetermined using accepted numerical methods for all test compoundsadministered. For example, see R. E. Kirk (1982) “Experimental Design:Procedures for the behavioral sciences,” 2nd ed. One method to establishthe significance of the analgesic activity of a given test compoundcompared to that of another is to calculate the SEM values for each ED₅₀value. If the SEM values do not overlap the line of addition, then theED50 values are significantly different from the line of addition.

[0261] Yet another accepted animal model to demonstrate the ability of aparticular compound to treat pain, or provide analgesic effects, is thewell known Rat Model of Carrageenan-induced Thermal Hyperalgesia, alsodescribed in published International Application WO 00/028980.

[0262] Carrageenan-induced Thermal Hyperalgesia in Rats

[0263] Another accepted method for detecting and comparing the analgesicactivity of different classes of analgesic compounds for which there isgood correlation with human analgesic activity is the reversal ofcarrageenan-induced thermal hyperalgesia in rats (Hargreaves et al. Pain32:77-88, 1988).

[0264] Rats are administered a dose test compound or vehicle and theninjected subcutaneously into one hindpaw, with carrageenan (1.5% w/v,100 μl). The response to noxious thermal stimulus is determined twohours later using a commercially available thermal plantar device (UgoBasil, Italy) according to established methods (Hargreaves et al. Pain32:77-88, 1988). Briefly, animals are habituated to a plastic behavioralenclosure for 5 min. A heat source is positioned directly beneath ahindpaw and the time taken for hindpaw withdrawal monitoredautomatically. If the animal does not respond within 20 sec, thestimulus is automatically terminated to prevent tissue damage.Measurements for both the injured and contralateral (control) hindpaware recorded. Thermal hyperalgesia is evidenced by a shorter responselatency by the injured as compared to the control paw. ED₅₀ values andtheir standard error of means (SEM) are determined using acceptednumerical methods. For example, see R. E. Kirk (1982) “ExperimentalDesign: Procedures for the behavioral sciences,” 2nd ed.

We claim:
 1. A compound of Formula:

wherein R¹ is H, CO₂H, tetrazole, OH, or (C₁-C₄)alkyltetrazole; R² is H,(C₁-C₆)alkyl, aryl, halo, CO₂H, (C₁-C₆)alkyl-heterocycle,(C₁-C₆)alkyl-(substituted)heterocycle, (C₁-C₄)alkyl-N—SO₂-aryl, NO₂,NH₂, CF₃, or (C₁-C₆)alkoxy carbonyl, NSO₂aryl; W, X, and Y eachindependently represent H, (C₁-C₆)alkyl, CO₂H, halo, OH, heterocycle,substituted heterocycle, CF₃, (CH₂)_(n)CO₂H, (C₁-C₆)alkoxy, or(C₁-C₆)alkoxy carbonyl; or optionally, X and R² together, along with thecarbon atoms to which they are attached, form a fused-benzo group, oroptionally, W and R¹ together, along with the carbon atoms to which theyare attached, form a fused-benzo group or a fused-triazole group, and is0, 1, or 2; or a pharmaceutically acceptable salt or prodrug thereof. 2.The compound according to claim 1 wherein W represents hydrogen.
 3. Thecompound according to claim 1 wherein X represents hydrogen.
 4. Thecompound according to claim 1 wherein Y represents hydrogen.
 5. Thecompound according to claim 1 wherein R² represents hydrogen.
 6. Thecompound according to claim 1 wherein R¹ represents tetrazole.
 7. Thecompound according to claim 6 wherein X and Y represent hydrogen.
 8. Thecompound according to claim 7 wherein R² represents hydrogen.
 9. Thecompound according to claim 8 wherein W represents hydrogen.
 10. Acompound which is (3S, 4aR, 6S, 8aR)6-(2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid or a pharmaceutically acceptable salt or prodrug thereof.
 11. Thecompound according to claim 10 wherein the pharmaceutically acceptablesalt is the dihydrochloride salt.
 12. The compound according to claim 8wherein W represents C₁-C₆alkyl.
 13. The compound according to claim 12wherein W represents Me.
 14. A compound which is (3S, 4aR, 6S, 8aR)6-(3-methyl-2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid or a pharmaceutically acceptable salt or prodrug thereof.
 15. Thecompound according to claim 14 wherein the pharmaceutically acceptablesalt is the dihydroiodide salt.
 16. The compound according to claim 14wherein the pharmaceutically acceptable salt is the dihydrochloridesalt.
 17. The compound according to claim 8 wherein W is Halo.
 18. Thecompound according to claim 17 wherein W is Cl.
 19. A compound which is(3S, 4aR, 6S, 8aR)6-(3-chloro-2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid or a pharmaceutically acceptable salt or prodrug thereof.
 20. Thecompound according to claim 19 wherein the pharmaceutically acceptablesalt is the dihydroiodide salt.
 21. The compound according to claim 19wherein the pharmaceutically acceptable salt is the dihydrochloridesalt.
 22. A compound of the Formula:

wherein R³ is hydrogen, (C₁-C₂₀)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkylaryl,(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-N,N—C₁-C₆ dialkylamine,(C₁-C₆)alkyl-pyrrolidine, (C₁-C₆)alkyl-piperidine, or(C₁-C₆)alkyl-morpholine; R⁴ is H, CO₂R⁶, tetrazole, OH, or(C₁-C₄)alkyltetrazole; R⁵ is H, (C₁-C₆)alkyl, aryl, halo, CO₂R⁷,(C₁-C₆)alkyl-heterocycle, (C₁-C₆)alkyl-(substituted)heterocycle,(C₁-C₄)alkyl-N—SO₂-aryl, NO₂, NH₂, CF₃, or (C₁-C₆)alkoxy carbonyl,NSO₂aryl; W′, X′, and Y′ each independently represent H, (C₁-C₆)alkyl,CO₂R⁸, halo, OH, heterocycle, substituted heterocycle, CF₃, (CH₂)nCO₂R⁸,(C₁-C₆)alkoxy, or (C₁-C₆)alkoxy carbonyl; R⁶, R⁷, and R⁸ eachindependently represent hydrogen, (C₁-C₂₀)alkyl, (C₂-C₆)alkenyl,(C₁-C₆)alkylaryl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-N,N—C₁-C₆dialkylamine, (C₁-C₆)alkyl-pyrrolidine, (C₁-C₆)alkyl-piperidine, or(C₁-C₆)alkyl-morpholine; or optionally, X′ and R⁵ together, along withthe carbon atoms to which they are attached, form a benzo-fused group,or optionally, W′ and R⁴ together, along with the carbon atoms to whichthey are attached, form a benzo-fused group or a triazole-fused group,with the proviso that where R⁴ is CO₂R⁶, or R⁵ is CO₂R⁷, or W′, X′, orY′ is CO₂R⁸ then at least one, but no more than two of R³, R⁶, R⁷, andR⁸ is other than hydrogen; or a pharmaceutically acceptable saltthereof.
 23. The compound according to claim 22 wherein R³ is C₁-C₂₀alkyl.
 24. The compound according to claim 23 wherein R³ is C₁-C₆ alkyl.25. The compound according to claim 24 wherein R⁴ is tetrazole.
 26. Thecompound according to claim 25 wherein R⁵ is hydrogen.
 27. The compoundaccording to claim 26 wherein X′ and Y′ are hydrogen.
 28. The compoundaccording to claim 27 wherein W′ is hydrogen.
 29. A compound which is2-ethyl-butyl (3S, 4aR, 6S, 8aR)6-(2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate,or a pharmaceutically acceptable salt thereof.
 30. The compoundaccording to claim 29 wherein the pharmaceutically acceptable salt isthe dihydrochloride salt.
 31. The compound according to claim 27 whereinW′ is C₁-C₆ alkyl.
 32. The compound according to claim 31 wherein W′ isMe.
 33. A compound which is 2-ethyl-butyl (3S, 4aR, 6S, 8aR)6-(3-methyl-2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate,or a pharmaceutically acceptable salt thereof.
 34. The compoundaccording to claim 33 wherein the pharmaceutically acceptable salt isthe dihydroiodide salt.
 35. The compound according to claim 33 whereinthe pharmaceutically acceptable salt is the dihydrochloride salt. 36.The compound according to claim 27 wherein W′ is Halo.
 37. The compoundaccording to claim 36 wherein W′ is Cl.
 38. A compound which is2-ethyl-butyl (3S, 4aR, 6S, 8aR)6-(3-chloro-2-(1(2)H-tetrazol-5-yl)-phenylamino)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylateor a pharmaceutically acceptable salt thereof.
 39. The compoundaccording to claim 38 wherein the pharmaceutically acceptable salt isthe dihydroiodide salt.
 40. The compound according to claim 39 whereinthe pharmaceutically acceptable salt is the dihydrochloride salt.
 41. Amethod of treating a neurological disorder or neurodegenerative diseasecomprising administering to a patient in need thereof, an effectiveamount of a compound according to claim
 1. 42. The method according toclaim 41 wherein the neurological disorder is pain or migaine.
 43. Amethod of treating a neurological disorder or neurodegenerative diseasecomprising administering to a patient in need thereof, an effectiveamount of a compound according to claim
 22. 44. The method according toclaim 42 wherein the neurological disorder is pain or migaine.
 45. Apharmaceutical composition comprising an effective amount of thecompound according to claim 1, in combination with a pharmaceuticallyacceptable carrier, diluent, or excipient.
 46. A pharmaceuticalcomposition comprising an effective amount of the compound according toclaim 22, in combination with a pharmaceutically acceptable carrier,diluent, or excipient.
 47. The use of a compound according to claim 1for the manufacture of a medicament for the treatment of pain ormigraine.
 48. The use of a compound according to claim 22 for themanufacture of a medicament for the treatment of pain or migraine. 49.The use of a compound according to claim 1 for the treatment of pain ormigraine.